tbuckley/cabot-search huggingface dataset:
Scenery of multilocus inherited neoplasia alleles syndrome (MINAS) in a single Brazilian institution.
Authors: Andre Marcio Murad, José Claudio Casali-da-Rocha, Juliana Garcia Carneiro
Journal: Journal of Clinical Oncology (2022)

10598 Background: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Methods: A cohort of 1,234 unrelated patients with suspicion of hereditary cancer was screened using a validated NGS panel including 20 genes associated with hereditary cancer. Results: One hundred and forty two (8.7%) patients harbouring probably pathogenic or pathogenic mutatations and 9 harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 6.3% (9/142) of patients with pathogenic mutations. All (9/9) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. Conclusions: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.
Overall survival (OS) and biomarker results from combat: A phase 2 study of bipolar androgen therapy (BAT) plus nivolumab for patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Mark Christopher Markowski, Mary-Ellen Taplin, Rahul Raj Aggarwal, Laura Sena, Hao Wang, Aliya Lalji, Jennifer Meyers, Alyza Skaist, Anuj Gupta, Carolina Gomes-Alexandre, Tracy Jones, Jessica Hicks, Sushant Kachhap, Srinivasan Yegnasubramanian, Angelo M De Marzo, Samuel R. Denmeade, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2022)

5064 Background: During BAT, intramuscular (IM) administration of testosterone (T) results in rapid cycling of serum T from supraphysiologic to near-castrate levels in men with mCRPC. In a retrospective study, clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT were observed. Here, we report the OS and biomarker results of a Phase 2 study in mCRPC pts treated with BAT in combination with nivolumab (COMBAT; NCT03554317). Methods: This was a multi-center, single arm, open label Phase 2 study in mCRPC pts who received T cypionate 400mg IM (BAT) every 28 days plus nivolumab 480mg IV every 28 days. Pts initially received BAT alone for a 12-week period, prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue metastases amenable to biopsy, and who progressed on at least one prior novel AR targeted therapy (and up to one prior chemo for mCRPC). The primary endpoint was confirmed PSA 50 response. OS and radiographic progression free survival (rPFS) were key secondary endpoints. All pts underwent baseline metastatic biopsies, and 24 had a second biopsy after 12 weeks of BAT. Semi-quantitative IHC (for AR, Ki67, MYC, PTEN, TP53, RB1) was performed on 24 paired biopsies, of which 15 pairs were also evaluable for RNA (whole transcriptome) sequencing. Results: 45 pts were enrolled. As previously reported, the PSA 50 response was 40% (18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis), and median rPFS was 5.6 (95% CI: 4.4–6.0) months. After a median follow-up of 17.8 months, the median OS was 27.8 (95%% CI: 17.6–NR) months. In 24 pts with paired biopsies prior to administration of nivolumab, BAT significantly decreased median MYC (P=0.046) and Ki-67 (P=0.030) expression by IHC. 71% (17/24) of pts had any decrease in MYC following BAT, with 29% (7/24) having a &gt;50% decrease. A &gt;50% MYC protein decline was associated with longer rPFS (HR 0.33, 95%CI 0.14–0.78, P=0.005) and a nonsignificant association towards longer OS (HR 0.78, 95%CI 0.24–2.48, P=0.679). MYC protein and mRNA levels were tightly intercorrelated (r=0.65, P&lt;0.001). Both rPFS and OS were numerically longer in pts with &gt;50% declines in MYC mRNA levels (P&gt;0.1 for both). Conclusions: BAT combined with nivolumab led to a median overall survival of &gt;2 years in heavily pretreated mCRPC pts. BAT attenuated MYC expression, correlating with better outcomes. Clinical trial information: NCT03554317.
Efficacy and safety of anlotinib with PD-1 blockades in the treatment of advanced biliary tract cancer: A real-world study.
Authors: Kehe Chen, Xianshi Huang, Lei Yu, Encun Hou, Mei Ou, Junping Wang, Xiao Huang, Deng Pan, Yu Liu, Min Huang, Wenhe Zhong, Zhuang Pan, Shijie Zhang, Bin Li, Xiansheng Nong, Kefan Chen
Journal: Journal of Clinical Oncology (2022)

e16129 Background: Several clinical trials have demonstrated that antiangiogenic drugs combined with PD-1 blockades are effective for patients with advanced biliary tract cancer (BTC). However, the efficacy of this combination in real-world patients needs to be explored. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. The aim of this study was to investigate the efficacy and safety of anlotinib combined with PD-1 blockades in the treatment of advanced BTC in real world. Methods: This is a multi-center prospective real-world study. Patients with advanced BTC receiving anlotinib combined with PD-1 blockades were recruited. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigator according to RECIST version 1.1. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: From May 2020 to Sep 2021, a total of 14 eligible pts were recruited. 1 patient was in stage IIIa, 4 pts in stage IIIb, and 9 pts in stage IV. Among them, 10 pts received anlotinib as first-line treatment, 3 pts as second-line treatment and 1 pts as third-line treatment. DCR was 85.71% (57.19%, 98.22%). At the data cut-off date, 7 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median OS was 8.21 months (95%CI: 5.88, NA) and the median PFS of the 14pts was 6.28 months (95%CI: 3.17-8.21). The safety profile suggested that the most common drug-related adverse events were hypertension (21.43%), decreased white blood cell count (21.43%), decreased platelet count (21.43%), hypoalbuminemia (14.29%), vomit (14.29%), gastrointestinal bleeding (14.29%). The common grade 3 adverse event were gastrointestinal bleeding (7.14%), anemia (7.14%), biliary infection (7.14%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 blockades exhibited potential efficacy and manageable adverse events in the treatment of advanced BTC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521.
<i>KRAS</i> mutation detection and cfDNA in liquid biopsy as prognostic factors in pancreatic adenocarcinoma.
Authors: Carles Fabregat-Franco, Judit Matito, Agatha Martin, Helena Verdaguer, Florian Castet, Josep Maria Miquel Aymar, Gloria Castillo, Alexandre Sierra, Ana Vivancos, Teresa Macarulla
Journal: Journal of Clinical Oncology (2022)

e16302 Background: Approximately 80% of pancreatic ductal adenocarcinoma (PDAC) patients present with advanced disease at diagnosis, with a 5-year survival rate of less than 5%. According to molecular profiling, mutations in KRAS have been described in 90% of PDAC patients, and correlated with poor prognosis. Nevertheless, the invasiveness of tumor biopsy and the difficulties in obtaining quality samples in some patients remains a concern. Circulating free DNA (cfDNA) is considered a surrogate marker of tumor burden and may also act as a prognostic factor that can be used independently from tumor biopsy. In this study, we aim to explore molecular prognostic biomarkers using plasma samples. Methods: Patients with metastatic PDAC harboring KRAS mutation in tissue samples and treated with first-line chemotherapy were identified at Vall d’Hebron University Hospital. Clinical features and plasma samples were collected before starting any treatment. DNA mutations were analyzed in plasma and compared with tissue samples. In plasma, detection of KRAS mutation and total cfDNA concentration were evaluated for clinical significance. A cfDNA minimum 100 genome equivalent threshold was proposed based on results and utility. A Chi-square test was planned to prove the independence between cfDNA levels and KRAS detection in plasma. Survival analysis was performed using the Kaplan-Meier method. Results: We included 33 PDAC patients with a median age of 66.1 years old, 57% were women. All of them were treated with gemcitabine and Nab-paclitaxel. At the final analysis cut-off, 31 patients had died . KRAS mutation was detected in 25 patients’ blood samples (75.8%) and cfDNA-High levels were considered for 20 patients (60.6%). 19 of 20 (95%) patients with cfDNA-High correlated with KRAS blood detection, showing significant dependence (p-value 0.001). Median overall survival (OS) was 10.5 months in the KRAS detected group compared with 22.6 months in the KRAS non-detected group (HR for death 4.70; confidence interval (CI) 1.70-12.98, p-value 0.002). Better separation was seen using cfDNA where median OS was 9.8 months in the cfDNA-High group compared with 21.0 months in the cfDNA-Low group (HR for death 5.38; CI 2.17-13.31, p-value &lt; 0.001). Conclusions: Liquid biopsy can provide quality prognostic information in metastatic PDAC patients. On account of this, the cfDNA level is proposed as a prognostic factor. However, prospective cohorts to validate this information are needed.[Table: see text]
Impact of weekend effect on neutropenic fever admissions associated with malignancy.
Authors: Sandhya Shri Kannayiram, Aathi Lakshmi Mariappan, Palak Desai
Journal: Journal of Clinical Oncology (2022)

e18658 Background: The impact of the “weekend effect” (increased mortality rate during Saturday and/or Sunday admissions) on hospitalizations for various medical emergencies has been studied with results often showing adverse patient outcomes. Febrile neutropenia in cancer patients is an acute oncological emergency with significant mortality and morbidity. Here, we attempt to explore if the day of admission impacts outcomes and healthcare utilization in cancer patients admitted for neutropenic fever. Methods: We performed a retrospective analysis using the National Inpatient Sample (NIS) database from 2019, and identified all adult admissions with cancer (hematological and solid cancers) and a concomitant primary or secondary diagnosis of Febrile Neutropenia using ICD 10 codes. These patients were divided based on the day of admission (group 1: weekday vs. group 2: weekend). The groups were compared for demographic differences, inpatient mortality, length of stay (LOS), and hospital charges (TCHG). Secondary outcomes studied were complications like sepsis, septic shock (SS), and mechanical ventilation (MV). Statistics were performed using the t-test, chi-square test, multivariate logistic analysis. Results: A total of 136,895 cancer patients were admitted with febrile neutropenia, and of those, 28,559 patients were admitted during the weekend. Both groups had similar demographics (p = &gt; 0.05) with a mean age of 61 years, more males (52% vs. 51%), admitted in large-sized and urban teaching hospitals, and a majority had Medicare insurance (48% vs. 50%). 4.6% of weekday and 4.7 % of the weekend admissions died during hospitalization. Weekend admissions were likely to have a slightly lower mortality, although not statistically significant(aOR = 0.96,95% CI = 0.81-1.1, p = 0.72). The mean LOS was 9 days for group 1 and 8 days for group 2 (p &lt; 0.001*). TCHG was lower for the weekend by $ 15,770 per admission (p &lt; 0.001*). The rates and odds of having sepsis, SS, MV were similar between both groups (p &gt; 0.05). In addition, increasing age, Hispanic race, and comorbid chronic kidney disease, diabetes, congestive heart failure, acute kidney injury, acute respiratory failure resulted in higher mortality, LOS, and all complications (p = &lt; 0.001*) regardless of the day of the admission. Conclusions: The mortality rate and other outcomes in neutropenic fever did not statistically change between weekday and weekend admissions. Interestingly, the healthcare resource utilization (LOS and TCHG) was higher on weekdays. It is encouraging to note that the “weekend effect” has not impacted the in-hospital outcomes. However, patients admitted with febrile neutropenia have a high mortality rate and increased risk of serious complications. Therefore, utmost vigilance and close follow-up are necessary when treating these patients. *p = &lt; 0.05 was considered significant; aOR = Adjusted Odds Ratio.
Atrial fibrillation is associated with worse outcomes in patients with breast cancer.
Authors: Mohamed M. Gad, Anas M. Saad
Journal: Journal of Clinical Oncology (2022)

e13043 Background: The incidence of atrial fibrillation (AF) is higher in women with breast cancer (BC) compared to aged-matched controls. A better understanding of the clinical outcomes in women with BC and AF can help stratify patients’ risk and inform clinical decision making. Methods: Females with active BC diagnosis hospitalized from January 2010 to December 2018 for any cause were identified in the Nationwide Readmissions Database (NRD). Hospitalizations were divided to females with AF and those without a known diagnosis of AF. The primary outcome was in-hospital mortality. Multivariate logistic regression analysis was performed to adjust for differences in baseline characteristics. All statistical analyses were conducted using the weighted values of observations as provided by the NRD to measure national estimates. Results: A total of 1,596,853 hospitalizations of BC were identified. Out of those, 119,307 (7.5%) had AF. Females with AF were older, median age 77 [IQR 69-84] versus 61 [51-71]. AF patients had higher rates of chronic pulmonary disease, 23.0% versus 14.3%, p &lt; 0.001; hypothyroidism, 20.9% versus 13.1%, p &lt; 0.001; peripheral vascular disease, 6.8% versus 2.5%, p &lt; 0.001; pulmonary hypertension, 4.8% versus 1.6%, p &lt; 0.001; cardiac valvular disease, 9.5% versus 2.3%, p &lt; 0.001; hyperlipidemia, 39.9% versus 24.0%, p &lt; 0.001; diabetes mellitus, 28.9% versus 19.8%, p &lt; 0.001; heart failure, 37.0% versus 7.5%, p &lt; 0.001; prior bypass surgery, 4.1% versus 1.2%, p &lt; 0.001; prior stroke, 7.8% versus 2.5%, p &lt; 0.001; and prior myocardial infarction, 6.0% versus 2.2%, p &lt; 0.001. In-hospital mortality was significantly higher in patients with AF, 7.1% versus 4.1%, p &lt; 0.001. Adjusted Odds Ratio (aOR) for in-hospital mortality was higher in AF, aOR 1.42, 95% CI (1.38-1.46), p &lt; 0.001. Conclusions: Atrial fibrillation is associated with a higher risk of in-hospital mortality in patients with breast cancer regardless of the reason of hospitalization. Stratifying patients based on AF presence can help inform clinicians and patients of the patients’ risk of mortality during hospitalization.
ScRNA-seq based copy number variations (CNVs) detection identified TPSB2 and TPSAB1 as prognostic biomarkers in Gastric Cancer(GC).
Authors: Tao Wang, Liuqing Zheng, Qian Wang, Shanshan Xiao
Journal: Journal of Clinical Oncology (2022)

e16021 Background: Gastric Cancer (GC) is the third leading cause of cancer-related mortality around the world, with a relatively poor prognosis. Single-cell RNA-sequencing (scRNA-seq) is a powerful tool to analyze tumor microenvironment at a comprehensive resolution, revealing previously uncharacterized molecular complexities. CNVs detection based on scRNA-seq data can reveal genome heterogeneity, therefore identify prognostic biomarkers at the single cell level. Methods: ScRNA-seq data from publicly available dataset (Anuja S et.al, CCR 2020) with 3 gastric cancer tissues, and 3 paired adjacent normal tissues was used. We inferred CNVsusing non-malignant cells as reference to estimate the mutations of malignant cells based on InferCNV package. Survival analysis was made by Kaplan-Meier method on TCGA-STAD (Stomach adenocarcinoma) cohort to identify the CNV genes with prognostic ability. To further explore these genes, their correlations with CD8+T cells marker ( CD8A) and malignant marker ( EPCAM) were analyzed based on the Spearman Correlation Method. Results: From a total of 11,459 cells, comprising 3 gastric cancer tissues (7,634 cells), and 3 paired adjacent normal tissues (3,825 cells), we identified 23 clusters that belonged to different types of cells including Endothelial, Epithelial, Fibroblast, B cells, Myeloid cells, T cells and NK cells. InferCNV analysis predicted 5 CNV regions and 209 CNV genes according to the heterogeneity between malignant and non-malignant cells. Survival analysis based on RNA-seq data from TCGA-STAD cohort, enabled us to narrow down the list of candidate biomarkers to 22 genes with prognostic ability. Among them, the specific functions of TPSB2 and TPSAB1 in GC, especially in their prognosis value, remain unclear. Downregulations of these 2 genes were both associated with longer progression-free survival (PFS). More specifically, expression profiles of gene TPSB2 and TPSAB1 were positively correlated with Epithelial marker genes (p = 0.02 and 0.03 respectively) but negatively correlated with CD8+ T lymphocytes (p = 0.02 and 0.11 respectively). Conclusions: Our analysis suggested that the high expressions of gene TPSB2 and TPSAB1 are associated with poor prognosis in GC patients. And these two genes are correlated with low T lymphocyte infiltration and an immune-suppressive environment, which could be possible prognosis biomarkers to identify patients with a more aggressive tumor evolution.
Beyond BCMA: Outcomes of relapsed/refractory multiple myeloma after progression on anti-BCMA T cell redirecting therapy.
Authors: Sankalp Arora, Smith Giri, Kelly Nicole Godby, Gayathri Ravi, Luciano J. Costa, Susan Bal
Journal: Journal of Clinical Oncology (2022)

e20026 Background: Immunotherapeutic strategies targeting B-cell Maturation Antigen (BCMA) have revolutionized the management of triple class refractory multiple myeloma (MM). However, the outcomes of patients (pts) who experience progressive disease (PD) after anti BCMA T-cell redirecting therapy (TRT) are unknown. Methods: We retrospectively analyzed pt and disease characteristics as well as post-BCMA outcomes for adults with relapsed/refractory MM who experienced PD after BCMA TRT at our institution. Responses were assessed by International Myeloma Working Group criteria. Survival outcomes were measured using Kaplan-Meier estimator. Results: Between 8/2018-2/2022, 63 pts received anti-BCMA TRT. With median follow up of 11.3 months (mos), 25 pts (40%) remain alive without MM progression and 7 pts (11%) died without progression. A total of 31 pts experienced PD and are the subject of this analysis. The median time from diagnosis to BCMA TRT was 36 mos with median 6 prior LoT (3-11) and 81% penta-refractory. The median time from BCMA TRT (CAR-T in 61%, bispecific T-cell engager in 39%) to post-BCMA PD was 3.19 mos. Overall response rate (ORR) to BCMA TRT for these 31 pts was 52% (≥very good partial response; VGPR 39%). Among the pts with post-BCMA PD, 45% had high risk cytogenetics (CHR), 45% extramedullary plasmacytomas (EMP), and 81% penta-refractory disease. The median overall survival (mOS) from time of post-BCMA PD is 4.3 mos (median follow up 8 mos). Eight pts with PD were not candidates for additional therapy and had mOS of 1 mo. The remaining 23 pts with PD were able to receive 1 or more additional LoT. For this group, median age was 64 years (42-77), 70% male, 52% had CHR, 22% ISS stage III. The median prior LoT was 6 (3-11) and 74% were penta-refractory. Median time from initiation of BCMA TRT to start of first post BCMA therapy was 4.3 mos (0.6-17). The most commonly used agents in next LoT are shown in the table. ORR to subsequent LoT was 35% (17% ≥VGPR). With 5 mos median follow up, 13 pts (57%) have died, median PFS and mOS to 1 st post BCMA LoT is 2.2 mos and 8.1 mos. Eight pts were able to proceed with experimental therapies (88% non-BCMA TRT) with higher ORR 50% (25% ≥VGPR) resulting in longer mPFS (3.3 mos) and mOS (11 mos) with median follow up of 10.9 mos. One pt received BCMA directed CAR-T after progression on anti-BCMA T-cell engager and did not respond. Conclusions: The outcomes of pts progressing on BCMA TRT remain poor. However, failure of BCMA targeting TRT does not preclude response to T-cell engagers against non-BCMA targets. Participation in clinical trials evaluating novel mechanisms remains the best strategy for this challenging population.[Table: see text]